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Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression
- Source :
- Clinical Cancer Research, 23(14), 3721-3733. American Association for Cancer Research Inc., Clinical cancer research, 23(14), 3721-3733. American Association for Cancer Research Inc., Clinical Cancer Research, 23(14), 3721-3733, Baglio, S R, Lagerweij, T, Pérez-Lanzón, M, Ho, X D, Léveillé, N, Melo, S A, Cleton-Jansen, A M, Jordanova, E S, Roncuzzi, L, Greco, M, Van Eijndhoven, M A J, Grisendi, G, Dominici, M, Bonafede, R, Lougheed, S M, De Gruijl, T D, Zini, N, Cervo, S, Steffan, A, Canzonieri, V, Martson, A, Maasalu, K, Köks, S, Wurdinger, T, Baldini, N & Pegtel, D M 2017, ' Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression ', Clinical Cancer Research, vol. 23, no. 14, pp. 3721-3733 . https://doi.org/10.1158/1078-0432.CCR-16-2726
- Publication Year :
- 2017
-
Abstract
- Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets. Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)–educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography. Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGFβ, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGFβ-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGFβ are increased in osteosarcoma patients. Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGFβ-blocking agents as new therapeutic options for osteosarcoma patients. Clin Cancer Res; 23(14); 3721–33. ©2017 AACR.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Pathology
Lung Neoplasms
Exosomes
Mice
Transforming Growth Factor beta
Osteosarcoma
Tissue microarray
biology
Extracellular vesicle
Gene Expression Regulation, Neoplastic
Mesenchymal Stem Cell
Oncology
EV-associated TGFβ
Cells
Recipient cells
Female
tumor extracellular vesicle (EV)–educated mesenchymal stem cells (TEMSC)
Human
Signal Transduction
STAT3 Transcription Factor
musculoskeletal diseases
medicine.medical_specialty
Extracellular Vesicle
Antibodies, Monoclonal, Humanized
Extracellular Vesicles
tocilizumab
03 medical and health sciences
Stroma
Cell Line, Tumor
medicine
Animals
Humans
Cell Proliferation
therapy
business.industry
Animal
Interleukin-6
Mesenchymal stem cell
Cancer
Mesenchymal Stem Cells
Transforming growth factor beta
Gene signature
medicine.disease
Lung Neoplasm
Exosome
Disease Models, Animal
030104 developmental biology
Tissue Array Analysis
biology.protein
Cancer research
Cell
business
Tissue Array Analysi
osteosarcoma
Subjects
Details
- Language :
- English
- ISSN :
- 10780432 and 37213733
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research, 23(14), 3721-3733. American Association for Cancer Research Inc., Clinical cancer research, 23(14), 3721-3733. American Association for Cancer Research Inc., Clinical Cancer Research, 23(14), 3721-3733, Baglio, S R, Lagerweij, T, Pérez-Lanzón, M, Ho, X D, Léveillé, N, Melo, S A, Cleton-Jansen, A M, Jordanova, E S, Roncuzzi, L, Greco, M, Van Eijndhoven, M A J, Grisendi, G, Dominici, M, Bonafede, R, Lougheed, S M, De Gruijl, T D, Zini, N, Cervo, S, Steffan, A, Canzonieri, V, Martson, A, Maasalu, K, Köks, S, Wurdinger, T, Baldini, N & Pegtel, D M 2017, ' Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression ', Clinical Cancer Research, vol. 23, no. 14, pp. 3721-3733 . https://doi.org/10.1158/1078-0432.CCR-16-2726
- Accession number :
- edsair.doi.dedup.....f6fc995d21f815df8513d6bb494316e5